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Big Pharma Looks Beyond Insulin


After Geoffrey Forman was diagnosed with diabetes in 1988, every meal became a harrowing ordeal. His blood sugar often spiked to abnormal highs, and then to dangerous lows after he injected his insulin. He would break out in a sweat and become so light-headed he would practically faint. Then, in 1999, he entered a clinical trial for a drug called Symlin, a synthetic version of a natural hormone that works with insulin to control blood sugar. The roller-coaster of highs and lows ended. "This drug gave me a license to eat and not worry about it," says Forman, a computer consultant in Washington. "It adds normalcy to my life."

Symlin is aimed at type 1 diabetics -- those who must inject insulin several times a day because their bodies have stopped producing the vital hormone. The drug, developed by San Diego's Amylin Pharmaceuticals Inc., is expected to be approved by the Food & Drug Administration by Dec. 16. If it is, it will offer patients with type 1 diabetes the first completely new compound for treating their disease since insulin hit the market in the 1920s.

Symlin could be the first in a wave of new drugs to treat diabetes and other diseases that result when the body's metabolism goes haywire. Many companies, including Amylin, are developing drugs for the common type 2 form of diabetes, which occurs when the body does not make enough insulin or just stops responding to it. And some are mapping out new drug assaults on obesity itself -- a leading cause of type 2 diabetes, congestive heart failure, high blood pressure, and countless other health scourges. Such drug strategies have a wretched track record, but that hasn't stopped biotechs and giants such as Britain's GlaxoSmithKline PLC (GSK) from making obesity a priority -- along with diabetes. Glaxo alone has more than a half-dozen such drugs in its pipeline.

BATTLE OF THE BULGE

The FDA is sure to take these efforts seriously. In June, FDA Commissioner Mark McClellan announced that the fast-track approval process normally reserved for cancer treatments would also be applied to some obesity and diabetes drugs. And no wonder: More than 60% of Americans are overweight or obese. Diabetes now affects 18 million adults in the U.S. -- nearly twice the number 10 years ago -- and costs the economy $132 billion a year in lost productivity and medical bills.

Many of the emerging drugs are designed to replace hormones that patients with metabolic disorders don't produce themselves. Amylin, for example, is also testing a drug for type 2 diabetes, called Exenatide, which was derived from a hormone in the saliva of Gila monsters. The substance mimics a human hormone that stimulates insulin production. In trials, both drugs controlled the blood sugar while allowing patients to keep their weight steady. Some even lost a few pounds. "The drugs seem to make patients feel more satiated, which prevents them from overeating," says Dr. Athena Philis-Tsimikas, chief medical director of clinical operations for the Whittier Institute in San Diego, one of the testing sites for Symlin and Exenatide. Analysts expect peak annual sales of Symlin to range from $300 million to $500 million, and they believe Exenatide sales could top $1 billion.

Beyond such hormonal approaches are hundreds of new compounds for diabetes and obesity under study at universities and pharmaceutical labs around the world. Yet it could be a long and arduous path from mouse cages to FDA approval. The field is littered with examples of drugs that worked well in animals but proved unsafe or ineffective in humans. Most researchers remember Fen-Phen, the vaunted weight-loss drug that crashed when some patients developed heart defects -- showing just how hard it is to change a person's metabolism without risking dire side effects.

Such setbacks haven't deterred scientists from trying to conquer metabolic disease, however. One promising molecule under study has a name no layman will ever love: Peroxisome Proliferator-Activated Receptor (PPAR). There are three types of PPARs, which are proteins that control how the body absorbs, stores, and distributes fat. Researchers have learned to switch on and off the genes that produce these proteins. In a recent study at the Salk Institute for Biological Studies in San Diego, scientists stimulated a gene that produces one type of PPAR in a group of mice. Those mice soon weighed 20% less than normal mice. Predicts Ronald M. Evans, who led the study: "PPARs will be a revolutionary step in treating obesity and related diseases."

THREE IN ONE

The promise of PPARs has already proved useful in other metabolic disor- ders, including diabetes. GlaxoSmithKline's top-selling PPAR-based drug for diabetes, Avandia, helps make the cells in the body more sensitive to insulin, which in turn controls blood sugar in some people with type 2 diabetes. In the first nine months of this year, sales of Avandia surged 27% over the same period last year, to $1.2 billion.

Avandia, however, is no miracle drug. It actually makes patients gain weight and retain water. What's required, Glaxo scientists now believe, is a molecule that could target all three types of PPARs, rather than just the one that Avandia hits. "That way, we can mimic a more natural stimulation of these receptors," says Ken Batchelor, a senior vice-president at Glaxo. In animal trials of a three-in-one drug candidate, he says, "we don't see weight gain, we don't see fluid retention, and we see a great lowering of fats."

Not all of the new compounds will make it through the regulatory process unscathed. Amylin learned this lesson the hard way. In early studies, the company discovered that patients taking Symlin sometimes experienced dangerous blood-sugar lows when they started injecting the new drug -- if they didn't decrease the amount of insulin they were taking. After Amylin first applied for approval in 2001, the FDA demanded that the company launch an additional study to demonstrate exactly how Symlin and insulin should be dosed for optimal safety. "We were disappointed, but it was a reasonable request," concedes Daniel M. Bradbury, Amylin's chief operating officer. Such hurdles aside, physicians believe the drug industry will soon deliver better treatments for metabolic disorders. For obese America, it's not a minute too soon. By Arlene Weintraub in San Diego


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